Peritoneal dialysis and neurological outcome in infants and small children

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From the Pediatric Graduate School Children’s Hospital University of Helsinki

Helsinki Finland

Peritoneal dialysis and

neurological outcome in infants and small children

hanne laakkonen

ACADEMIC DISSERTATION

To be presented, with the permission of the Medical Faculty of the University of Helsinki, for public examination in the Niilo Hallman Auditorium,

Children’s Hospital, on 19^th of August 2011, at 12 noon.

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Supervised by Professor emeritus Christer Holmberg

Department of Pediatric Nephrology and Transplantation Children’s Hospital

Helsinki University Central Hospital Helsinki, Finland

and

Docent Kai Rönnholm

Department of Pediatric Nephrology and Transplantation Children’s Hospital

Reviewed by Docent Agneta Ekstrand Division of Nephrology Department of Medicine

and

Docent Kai Eriksson

Department of Pediatric Neurology Tampere University Hospital Tampere, Finland

Official opponent Professor Johan Vande Walle UZG Pediatrics University Hospital Gent, Belgium

ISBN 978-952-10-7094-5 (Paperback) ISBN 978-952-10-7095-2 (PDF) http://ethesis.helsinki.fi

Unigrafia Oy University Printing House Helsinki 2011

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To families with a child with a chronic kidney disease

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abstract

Background and aims. Improved outcomes for children on peritoneal dialysis (PD) have been evident in recent years due to advances in medical care. However, the youngest patients, infants and small children, continue to demonstrate inferior growth, more frequent infections, and higher mortality compared to older children. Moreover, maintaining normal intravascular volume status, especially in young anuric patients, has proven difficult. There are relatively many children needing dialysis in infancy in Finland compared to other countries due to the high prevalence of congenital nephrotic syndrome of the Finnish type (NPHS1, CNF). While the youngest patients form the greatest challenges in PD treatment, the risk for neurological sequelae is higher than in older children. However, the neurodevelopment of infants and small children on PD is a rarely reported topic. This study was designed to treat and monitor these youngest PD patients with a strict protocol, to critically evaluate the results, and finally to improve metabolic balance, growth and development in infants and small children during PD.

Methods. A retrospective analysis of 23 children under two years of age at onset of PD (mean 0.4 years), treated between 1995 and 2000, was performed in the first study to obtain a control population for our prospective study. Data about diagnoses, dialysis period, medication, laboratory parameters, complications, and growth was collected from patient records.

For the second and third studies, 21 patients less than two years of age at the beginning of PD (mean 0.6 years) were enrolled in our prospective protocol between 2001 and 2005.

In the second study, medication for uremia and nutrition were carefully adjusted during PD. Laboratory parameters and metabolic controls were regularly analyzed. To evaluate the intravascular volume status, blood pressure measurements, echocardiography, and analysis of N-terminal atrial natriuretic peptide (ANP-N) were performed. Growth before and during PD was analyzed and compared with midparental height. In the third study, the risk factors for development and the neurological development of these patients was determined. A neurologist, a physiotherapist and an occupational therapist evaluated all patients regularly during PD. The brain images taken before PD, during PD, and two years after renal transplantation (Tx) were surveyed. Hearing was tested during PD; in children at least three years old at the end of the study the hearing was tested also after renal Tx. Neuropsychological tests in children at least five years of age before the end of this study were collected and assessed.

In the fourth study, the data of six NPHS1 patients with a congruent neurological syndrome was analyzed. All these patients, born between 1984 and 2003, had a serious dyskinetic cerebral palsy-like syndrome with muscular dystonia and athetosis (MDA).

They also had a hearing defect. The brain MRI showed increased signal intensity in T2-weighted images in the globus pallidus area and their neurological symptoms were detected before the age of one year. The analysis of mitochondrial DNA (mtDNA) in these NPHS1 patients with MDA was performed in order to find a possible genetic

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Results. Hospitalization time was clearly shorter in the prospective PD patient group (65 days per patient-year) compared to the retrospectively analyzed patient group (124 days per patient-year). Metabolic control was mainly good in both patient groups.

However, the control of plasma intact parathyroid hormone level (iPTH) was very demanding. Furthermore, in the prospective patient group, although a mean weekly urea Kt/V of over 3.0 was achieved, the target of a mean creatinine clearance (Crcl) of over 65 L/week per 1.73 m²was very difficult, even impossible to achieve. It seems that a Crcl level of 40 L/week per 1.73 m² is acceptable in this age group.

The peritonitis rate diminished, it was 1 per 17.8 patient-months in the prospective patient group versus 1 per 14.5 in retrospectively analyzed patients, although this difference was not statistically significant. Hypertension was common in retrospectively analyzed patients; 70% had antihypertensive medication while in the prospective patient group only 33% had antihypertensive medication at some point during PD.

Thus, prospective patients received antihypertensive medication less frequently, but long-term hypertension was still seen in 43% during PD. Left ventricular hypertrophy decreased during the prospective study period. None of the patients in either group had pulmonary edema or dialysis-related seizures. Growth was good in most patients in both patient groups. Catch-up growth was documented in 64% of the retrospectively analyzed patients and in 57% of the prospective patients during dialysis. However, the prospective PD patients clearly lagged behind their midparental height at the end of PD. Mortality was 5% in the prospective PD patient group, and 9% in the retrospective PD patient group.

In the prospective PD patient group 11 patients (52%) had some risk factor for their neurodevelopment originating from the predialysis period. The neurological problems, detected before PD, did not worsen during PD and none of the patients developed new neurological complications during PD. Brain infarcts were detected in four patients (19%) and other ischemic lesions or periventricular leukomalasia (PVL) in three patients (14%). At the end of this study, 29% of the prospectively followed patients had a major impairment of their neurodevelopment and 43% only some minor impairment.

In the NPHS1-patients with MDA, neither mtDNA mutations nor external neurological complications could be found that could explain the symptoms. Thus, the reason for the neurological syndrome remains a mystery. Kernicterus was contemplated to be causative in the hypoproteinemic newborns but it could not be proven. Mortality was as high as 67% in this patient group during the whole follow-up period.

Conclusions. Our results for young PD patients were promising. Metabolic control was acceptable, growth was good, and mortality was low, however control of their calcium-phosphorus status proved demanding. Their peritonitis rate was about the same as for older children, whilst the high incidence of blood pressure proved problematic and several instruments were needed for examining and managing their intravascular volume status. Even if growth was good during PD, the children were significantly smaller compared to their midparental height. Although many patients were found to have neurological impairment at the end of our follow-up period, PD was a safe

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treatment for end-stage renal failure (ESRF) in infants and small children whereby their neurodevelopment did not worsen.

Key words: peritoneal dialysis, congenital nephrotic syndrome of the Finnish type, NPHS1, neurodevelopment, risk factors, blood pressure, motor development, brain imaging, intravascular volume status, hypervolemia, neurological development, infants, adequacy of dialysis, metabolic control, growth, midparental height.

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list of original publications

This thesis is based on the following original publications, which will be referred to in the text by their Roman numerals:

I Laakkonen H, Hölttä T, Lönnqvist T, Holmberg C, Rönnholm K. Peritoneal dialysis in children under two years of age. Nephrology Dialysis Transplantation 2008 May; 23(5):1747-53.

II Laakkonen H, Happonen J-M, Marttinen E, Paganus A, Hölttä T, Holmberg C, Rönnholm K. Normal growth and intravascular volume status with good metabolic control during peritoneal dialysis in infancy. Pediatric Nephrology 2010 25:1529- 1538.

III Laakkonen H, Lönnqvist T, Valanne L, Karikoski J, Holmberg C, Rönnholm K. Neurological development in 21 children on peritoneal dialysis in infancy.

Pediatric Nephrology (in press).

IV Laakkonen H, Lönnqvist T, Uusimaa J, Qvist E, Valanne L, Nuutinen M, Ala- Houhala M, Majamaa K, Jalanko H, Holmberg C. Muscular dystonia and athetosis in six patients with congenital nephrotic syndrome of the Finnish type (NPHS1).

Pediatric Nephrology 2006 21:182-189.

These articles were reprinted with the kind permission of their copyright holders.

Also some previously unpublished data are presented.

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abbreviations

AIMS Alberta Infant Motor Scale

ANP-N N-terminal atrial natriuretic peptide APD Automated peritoneal dialysis

AV Arteriovenous

BERA Brainstem evoked response auditory BIA Bioelectrical impedance analysis BOA Behavioral observation audiometry

BP Blood pressure

BSA Body surface area BUN Blood urea nitrogen

CAPD Continuous ambulatory peritoneal dialysis CaCO₃ Calcium carbonate

CCPD Continuous cycling peritoneal dialysis CKD Chronic kidney disease

CNF Congenital nephrotic syndrome of the Finnish type (NPHS1) CNS Central nervous system

CP Cerebral palsy Crcl Creatinine clearance CSF Cerebrospinal fluid CT Computerized tomography ECW Extra-cellular water EEG Electroencephalogram EF Ejection fraction EPO Erythropoietin

ERA-EDTA European Renal Association – European Dialysis and Transplantation Association

ESI Exit-site infection ESRF End-stage renal failure

FAO Food and Agriculture Organization of the United Nations FGF23 Fibroblast growth factor 23

FRKD Finnish Registry for Kidney Diseases hcfSDS Head circumference standard deviation score

HD Hemodialysis

HDL High-density lipoprotein hSDS Height standard deviation score ICW Intra-cellular water

IPP Intraperitoneal pressure iPTH Intact parathyroid hormone

KDOQI Kidney Disease Outcomes Quality Initiative

K Dialyzer clearance of the measured molecule in Kt/V Kt/V Dialysis clearance measure

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LDL Low-density lipoprotein

LVEDD Left ventricular end-diastolic dimension LVESD Left ventricular end-systolic dimension LVH Left ventricular hypertrophy

LVM Left ventricular mass LVMI Left ventricular mass index

LVPWD Left ventricular posterior wall thickness at end-diastole MDA Muscular dystonia and athetosis

MFED Munich Functional Developmental Diagnostic test MRI Magnetic resonance imaging

MtDNA Mitochondrial DNA

NAPRTCS North American Pediatric Renal Transplant Cooperative Study NEPSY Developmental Neuropsychological Assessment

NKF National Kidney Foundation NNR Nordic Nutrition Recommendation

NPHS1 Congenital nephrotic syndrome of the Finnish type (CNF) NPHS1 Nephrin gene

NS Nephrotic syndrome

(25-OH)D Calcidiol 1,25(OH)₂D Calcitriol

pmarp per million of age related population PTH Parathyroid hormone

PVL Periventricular leukomalacia PET Peritoneal equilibration test PD Peritoneal dialysis

RDA Recommended dietary allowance rhGH Recombinant human growth hormone RI Resistance index

RRF Residual renal function RRT Renal replacement therapy

SeptD Interventricular septal dimension at end-diastole SGA Small for gestational age

SNHL Sensorineural hearing loss

t Time in Kt/V

TBW Total body water

TEOAE Transient evoked otoacoustic emission TG Triglycerides

TI Tunnel infection TPD Tidal peritoneal dialysis Tx Transplantation

UF Ultrafiltration ULN Upper limit of normal UNU United Nations University

US Ultrasound

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V Volume of distribution in Kt/V

vs. Versus

WHO The World Health Organization

WISC Wechsler Intelligence Scale for Children

WPPSI Wechsler Preschool and Primary Scale of Intelligence

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1 introduction

The first successful kidney transplantation (Tx) in an adult was performed in 1954 in Boston, USA (Merril et al. 1956) and ten years later, the first adult patient received a renal transplant in Finland (Flatmark 1989). Progress in surgical techniques, treatment of complications, as well as better immunosuppressive medication, have nowadays made kidney Tx a valid therapy for end-stage renal failure (ESRF).

The active treatment of childhood uremia was started in the late 1960’s in Finland whereby some older pediatric patients even received kidney transplants in the adult unit. In 1971, the first small pediatric patient had a transplant operation at the Children’s Hospital, Helsinki University Central Hospital, without success due to inadequate immunosuppression. The patient was hemodialyzed before transplantation. Thus, in the beginning only a few older children with ESRF were actively treated in Finland (Hölttä 2000c). Renal Tx in the youngest patients remained a controversial matter globally (Chantler 1979). However, much progress has subsequently been made and infants are today also included in Tx programs. Extra peritoneal placement of the kidney is used for all pediatric patients in Finland. Their body weight must be over 9 kg, which is usually reached at about one year of age, before an adult size kidney can be successfully transplanted. Infants with ESRF typically require dialysis before Tx as an intermediate phase, always aiming at renal Tx.

Continuous ambulatory peritoneal dialysis (CAPD) was commenced in children in the 1970’s (Oreopoulos et al. 1979). In Finland, the first pediatric ESRF patients were treated with hemodialysis (HD) in units for adults. Peritoneal dialysis (PD) was introduced in pediatric patients in the early 1980’s and for infants in the late 1980’s (Hölttä 2000c). The latter group has been an especially challenging one because of the patients’ small size and problems with growth and development. Today, most pediatric ESRF patients in Finland are treated with PD, especially the youngest ones.

Because of a high incidence of congenital nephrotic syndrome of the Finnish type (NPHS1, CNF), more Finnish infants need renal replacement therapy (RRT) when compared to other countries (van der Heijden et al. 2004). Infections, poor growth and higher mortality in infants compared to older children and adults have been the major problems encountered during their PD (Warady et al. 1997, Verrina et al. 2004, Bunchman 1995, Neu et al. 2002, Shroff et al. 2006). The PD period has also been shown to be the most crucial time for complications in small children with ESRF. For instance, hemodynamic crises may lead to serious complications (Qvist et al. 2002).

Neurological development of infants and small children on PD has not been extensively reported but developmental delay is documented in 11 to 84% during ESRF and PD (Polinsky et al. 1987, Geary, Haka-Ikse 1989, Honda et al. 1995, Warady et al.

1999), although improvement was seen after Tx in one study (Polinsky et al. 1987).

The present study was developed to critically evaluate the nutrition, medication, PD treatment, metabolic balance, intravascular volume status, growth, and neurological development, in order to improve the overall treatment of infants and small children during PD.

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2 review of the literature

2.1 End-stage renal failure in children

End-stage renal failure (ESRF) is the stage of renal disease where the patients’ renal insufficiency has progressed so far that they cannot maintain their homeostasis and survive with their own renal function. At this point, renal replacement therapy (RRT), either dialysis or renal Tx, is needed (Harmon 1999).

2.1.1 Incidence

The incidence of ESRF in children under 5 years of age has increased significantly with time in Europe; in 1980―1984 the incidence was 2.4 per million of age related population (pmarp), in 1985―1990, was 6.2 pmarp, and in 1995―2000, was 8 pmarp.

However, in Finland the incidence of ESRF in children under 5 years was as high as 15.5 pmarp in 1995―2000 (van der Heijden et al. 2004) due to congenital nephrotic syndrome of the Finnish type (NPHS1, CNF). The incidence of NPHS1 is 1 in about 8200 live births in Finland (Huttunen 1976) which makes for a high proportion of small children in our ESRF population.

2.1.2 Etiology

The most prevalent diseases leading to ESRF in young children in Finland (Finnish Registry for Kidney Diseases 2009), compared to 29 European countries (van der Heijden et al. 2004), are presented in Table 1. Malformations of the kidney and urinary tract, such as urethral valves, are not specified in the European Registry, but in Finland they constitute 9% and 10% of diagnoses in patients under 2 and under 5 years of age.

table 1. Percentual proportions of renal diseases leading to ESRF in small children in Finland and Europe.

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2.1.2.1 Congenital nephrotic syndrome of the Finnish type

NPHS1 is the most comon diagnosis leading to ESRF in Finnish infants (Qvist et al.

2002, Hölttä et al. 1997). It is an autosomal recessive hereditary nephropathy with mutations in the nephrin gene NPHS1 (Holmberg et al. 2004). There are two main NPHS1 mutations (Fin-major and Fin-minor) in Finland which both cause a complete absence of nephrin in the glomerulus and a severe defect in the slit diaphragm, the important filter in the glomerulus, between the podocytes (Kestilä et al. 1998, Patrakka et al. 2000, Putaala et al. 2001). This leads to severe proteinuria already in utero and is lethal without active treatment in early childhood. The patients are nowadays mostly nephrectomized during their first year of life to avoid the massive proteinuria and its consequences (Holmberg et al. 1995).

2.1.3 Consequences of end-stage renal failure

ESRF and nephrectomy have several consequences for the patients’ health. The urinary excretion of phosphate decreases leading to hyperphosphatemia, active vitamin D diminishes, plasma calcium levels decrease, and all of these lead to increased parathyroid hormone (PTH) levels causing secondary hyperparathyroidism (see Fig.

3). These effects on bone cause high bone turnover and, with time, a bone growth disorder (Sanchez et al. 1999).

Fibroblast growth factor 23 (FGF23), a phosphatonin secreted by osteocytes and osteblasts when serum phosphate increases, has been actively studied recently. FGF23 appears to be one of the key molecules in the regulation of phosphate homeostasis. It increases the secretion of phosphate into urine and thus decreases serum phosphate levels. FGF23 expression is also regulated by vitamin D; administration of 1,25(OH)₂D, the active form of vitamin D, leads to increased levels of FGF23. Increasing FGF23 reduces 1α-hydroxylase activity leading to a decrease in 1,25(OH)₂D formation. This in turn increases PTH secretion (see Fig.3) (Silver, Naveh-Many 2010, Wesseling-Perry 2010, Yu et al. 2005, Isakova, Wolf 2010, Jüppner 2011).

Renal failure leads to metabolic acidosis due to reduced excretion of hydrogen ions. Acidosis induces hyperventilation, disturbs the normal metabolism of bones (causing growth retardation), and impairs the function of several hormones such as glucocorticoids, PTH, thyroid hormone and vitamin D (Mitch 2006). ESRF leads to high levels of waste products, such as urea nitrogen (BUN) and creatinine, cause many symptoms including nausea, fatigue, headache, and itching. Chronic uremia can also lead to more severe effects like pericarditis (Comty et al. 1971). Diminished production of erythropoietin in the kidneys leads to anemia (Wassner, Baum 1999). Anemia causes fatigue, dyspnea, deterioration of cognition, and stresses the heart among many other consequences. Edema and hypertension are also common findings in ESRF (Wassner, Baum 1999, Feld, Waz 1999, Haycock 1999).

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2.2 Treatment of end-stage renal failure

figure 1 Treatment of end-stage renal failure (ESRF).

2.2.1 Supportive treatment 2.2.1.1 Nutrition

Individualized nutritional counseling, frequent re-evaluations and modifications of the diet should be given to the PD patient and his/her family by a pediatric renal dietitian.

The age, development, and the family situation should be taken into account when planning the nutrition of each child (KDOQI Work Group 2009).

Energy requirements

Children with ESRF should get 100% of the estimated energy requirement for their age, adapted to the body size and physical activity level (KDOQI Work Group 2009).

In infants the daily energy intake should be roughly 80–90 kcal/kg. Additionally PD patients receive about 10 to 20 kcal/kg per day from dialysis fluids (Rönnholm, Holmberg 2006, Hölttä et al. 2000b). If energy intake is lower than recommended, tube feeding or a gastrostomy should be considered. The macronutrient distribution of the diet is directed to be as follows: carbohydrate 45–65%, fat 30–40%, and protein 5–20% in children between one and three years. In children under one year these ranges should be as in basic baby formulas: carbohydrate 36–56%, fat 40–54%, and 7–12% protein (KDOQI Work Group 2009).

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Protein supply

A report by a joint Food and Agriculture Organization, the United Nations (FAO)/

the World Health Organization (WHO)/ United Nations University (UNU) expert consultation, has defined the safe levels of protein supply (minimum) for each age- group (safe levels 1.09−1.86 g/kg per day) (World Health Organization 1985). The recommendation of the Kidney Disease Outcomes Quality Initiative (KDOQI) Work Group for dietary protein intake in small children is the daily recommended supply for a healthy child plus roughly 0.3 g/kg per day extra to replace losses due to dialysis (KDOQI Work Group 2009, Quan, Baum 1996). For children under seven months this is 1.8 g/kg per day, for children under 12 months 1.5 g/kg per day, and for children under four years of age 1.3 g/kg per day (KDOQI Work Group 2009). In infants, supplemental nutrients are needed to avoid fluid overload and to maintain a sufficient amount of energy and protein (Rönnholm, Holmberg 2006).

Fats

Suitable macronutrient distributions are given above. While cardiovascular diseases are the major cause of mortality and morbidity in children with ESRF the diet should be planned as to prevent increased plasma levels of triglycerides (TG) and cholesterol.

If fat supplementation to formula is needed, it should consist of unsaturated fats such as in canola, olive, soybean, or rape-seed oils. High amounts of cholesterol, saturated fat, or trans fatty acids in the diet may raise total cholesterol and low- density lipoprotein (LDL) cholesterol levels in blood. On the contrary, high dietary intake of polyunsaturated fatty acids such as eicosapentanoic acid (EPA), omega-3 fatty acids, and docosahexanoic acid (DHA) decrease TG levels in plasma. In case of hyperlipidemia (high LDL), the proportion of fat should be lower than usual (<30%

of calories), trans fatty acids should be avoided and saturated fatty acids should not exceed 7% of the calorie amount of the daily diet. In patients with high TG, in addition to low dietary fat and emphasis on polyunsaturated fatty acids, only a low quantity of simple carbohydrates should be served and complex carbohydrates favored (KDOQI Work Group 2009).

Micronutrients and vitamins

Very little is known about the vitamin and micronutrient requirements of children with chronic renal failure and during PD (KDOQI Work Group 2009, Rees, Shaw 2007).

In adult patients on PD, it has been shown that substitution with some water-soluble vitamins (C, B vitamins) is necessary to avoid vitamin deficiencies (Kopple et al.

1981, Ross et al. 1989, Blumberg et al. 1983). Dialysate losses are partly responsible for the increased need of these vitamins (Blumberg et al. 1983, Mydlik et al. 1985).

In children on PD, the blood concentrations of water-soluble vitamins have been shown to meet or exceed normal values with combined dietary and substitution intake (Kriley, Warady 1991, Warady et al. 1994). It has been suggested that children with chronic kidney disease should be given the same amount of vitamins as well as

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micronutrients and minerals as is recommended for healthy children (Rees, Shaw 2007). The KDOQI Work Group recommends offering 100% of the daily recommended intake for children with ESRF. If the dietary intake is below this goal, supplementary water-soluble vitamins should be given. Fat-soluble vitamins are normally not needed in addition to food intake if the patient stays on the planned diet (KDOQI Work Group 2009). In children on PD, low serum levels of copper, selenium, and zinc have been documented (Warady et al. 1994, Tamura et al. 1989, Zachara et al. 2006). KDOQI recommends that the levels of copper should be monitored every 4 to 6 months, and the recommended daily intake of copper, selenium and zinc should be provided (KDOQI Work Group 2009).

2.2.1.2 Medication

Treatment of secondary hyperparathyroidism

Secondary hyperparathyroidism is developed as a sum of many factors in chronic kidney disease (CKD) (see Figure 3). Treatment of hyperphosphatemia and hypocalcemia as well as supplementation with vitamin D in children with ESRF, are discussed in the next chapters.

figure 2 A) Pathogenesis of secondary hyperparathyroidism in chronic kidney disease.

Phosphate (Pi), calcium (Ca), serum vitamin 1,25(OH)2D, serum parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), FGF23 receptor (FGFR), calcium receptor (CaR), vitamin D receptor (VDR). The pathways that are disrupted in ESRF are marked with broken line arrows. B) In advanced chronic kidney disease such as ESRF, the

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Hyperphosphatemia

Hyperphosphatemia caused by diminished excretion of phosphate in the kidneys is first treated with dietary phosphate restriction. Traditional medications for hyperphosphatemia are calcium carbonate (CaCO₃) products, which bind to phosphate and reduce absorption of food phosphate in the intestine. At the same time, the patients receive calcium for their hypocalcemia. However, vascular calcification and higher incidence of cardiovascular disease compared to the general population have been reported in adults, as well as in childhood-onset ESRF (Querfeld 2004, Oh et al.

2002, Groothoff et al. 2005) Cardiovascular diseases are also a much more common cause of death compared to malignancies in patients transplanted during childhood (Offner et al. 1999). Sevelamer hydrochloride is used as a calcium free phosphate binder in grown-up patients, however in children, and especially in infants, sevelamer hydrochloride is scarcely used (Rees, Shroff 2010). Sevelamer hydrochloride often produces metabolic acidosis, which can be avoided by using sevelamer carbonate (Gonzalez et al. 2009). Nonetheless, today there are no calcium-free phosphate binders licensed for children (Rees, Shroff 2010) and the Kidney Disease Outcomes Quality Initiative (KDOQI) recommends that if sevelamer is used as the only phosphate binder in children, calcium should be supplemented with a calcium-including phosphate binder or/and a higher calcium concentration in the dialysate should be used (National Kidney Foundation (KDOQI) 2005).

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figure 3 Vitamin D and parathyroid hormone metabolism. Modeled after Deeb et al.

(2007). Negative feedback is indicated with a dashed line and diamond.

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Vitamin D substitution

The effects and metabolism of vitamin D in a healthy person are shown above in Figure 3. Vitamin D deficiency in ESRF originates from reduced or absent renal 1α-hydroxylation of vitamin 25-OH-D (calcidiol), which in healthy people is already 25-hydroxylated in the liver. Because of the 1α-hydroxylation defect, ESRF patients need vitamin D substitution as 1α-hydroxylated, 1α-hydroxycholecalsiferol (alphacalcidol) which is then hydroxylated in the liver to its active form 1,25(OH)2D (calcitriol), which may also be used as vitamin D substitute. Calcitriol increases the absorption of calcium and phosphate in the gut, increases bone mineralization and adjusts the level of serum calcium. Calcitriol provides negative feedback to PTH excretion thereby inhibiting the high bone turnover caused by high PTH. Providing an accurate dosage of alphacalcidol is challenging, because too high doses reduce PTH secretion, and over-suppression of PTH leads to adynamic bone disease, in which bone turnover is too low (Wesseling et al. 2008). Thus, to ensure good growth, the European Paediatric Dialysis Working Group recommends that in ESRF patients, the aimed level of plasma PTH should be two to three times the upper normal limit (Klaus et al. 2006).

Treatment of anemia

Erythropoietin (EPO) deficiency or relative deficiency, alterations in the activity of EPO caused by uremic toxins, and inhibition of erythroid progenitor cell formation in bone marrow are the most important factors causing anemia in children with ESRF (McGonigle et al. 1984, McGonigle et al. 1985). Regular erythropoietin injections and supplemental oral iron form the basis of anemia management in children with ESRF. In HD patients, the use of intravenous iron is preferred (KDOQI, National Kidney Foundation 2006). Infants require higher doses of EPO, from 275 to 350 U/

kg per week, compared to older children and adults. PD patients need less EPO than HD patients (NAPRTCS 2004 Annual Report 2005). Early EPO therapy has been associated with improved growth in children with chronic kidney disease (Boehm et al. 2007).

Treatment of hypertension

Hypertension has been observed in 55% of children during dialysis in Poland. The mean age of these patients was 10 ± 5 years and the hypertension incidence rate was similar in boys and girls (53 vs. 60%) as well as in PD and HP patients (54 vs. 56%).

Monotherapy was used in 33% and 36% received two antihypertensive drugs (Tkaczyk et al. 2006). In comparison, systolic hypertension was seen in 52% of Finnish children on PD and diastolic hypertension in 43%. Furthermore, 73% of children below five years of age had systolic hypertension. The antihypertensive medicines used in Finnish patients were mostly calcium channel blockers and β-blockers (Hölttä et al. 2001).

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2.2.2 Active treatment - dialysis

When renal function is severely reduced or absent, the tasks typically performed by the kidneys must be substituted. Their purification function and removal of excess water from the body are both managed by dialysis. Peritoneal dialysis (PD) and hemodialysis (HD) are common treatment possibilities, although hemodiafiltration may also be used in mainly acute situations.

In European ESRF patients under 5 years of age the first treatment modality has been PD in 70%, HD in 26% and pre-emptive renal transplantation in 4% according to the European Renal Association – European Dialysis and Transplantation Association (ERA-EDTA) report of 2004 (van der Heijden et al. 2004). In Finland, the percentages for the same age group between 1990 and 2008 were 97% for PD, 1% for HD and 2%

for pre-emptive transplantation (Finnish Registry for Kidney Diseases 2009).

The emphasis of this study is on PD treatment, and HD is discussed only briefly.

2.2.2.1 Peritoneal dialysis

Peritoneal dialysis has been used in children since the late 1970’s, starting in Canada (Oreopoulos et al. 1979). In Europe PD was later introduced and became an established treatment modality in children in the 1980’s (Alexander, Honda 1993). During PD, a dialysis solution (dialysate) is infused into the patient’s peritoneal cavity through a PD catheter and left there for a prescribed dwell time. The peritoneal membrane works as a semi-permeable filter through which water as well as urea, potassium, phosphate and other waste products diffuse from blood in the capillaries of the peritoneum into the dialysate to a lower concentration. Waste material is removed from the body by changing the dialysis solution several times per day to maintain the concentration gradient. The dialysate contains glucose, which creates an osmotic gradient between blood and dialysate. With this gradient, excess water is removed from the body. Small molecules such as urea move faster through the peritoneal membrane compared to larger molecules such as creatinine and phosphate (Gao et al. 2004).

The dialysate can be exchanged manually or with the help of a dialysis machine.

There are different kinds of PD machines with modern techniques, programs, and tubing suitable also for small children. At this moment Sleep●safe™ (Fresenius Medical Care, Bad Homburg, Germany), HomeChoice Pro (Baxter Healthcare Corp., Deerfield, IL, USA) and Serena® (Gambro AB, Stockholm, Sweden) are suitable machines for infants.

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figure 4 A) Principle of peritoneal dialysis. Adapted from Picsicio (http://picsicio.us/

image). B) X-ray image showing the right position of a PD catheter in the peritoneal cavity.

Access of PD

The access for PD, the catheter, is set into the peritoneal cavity through the abdominal wall. The implantation is recommended to be performed approximately two weeks prior to starting dialysis treatment, especially in children, to avoid leaks (Rönnholm, Holmberg 2006). Implantation should be carried out by experienced surgeons (Watson et al.

2001). According to the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) report 2007, most PD catheters used were the Tenckhoff curled (62%) or Tenckhoff straight (27%). Single-cuffs were present in about half of the catheters (53%), whilst 65% had a straight tunnel, and 40% of the exit-sites had a lateral orientation. There was no difference in the incidence of peritonitis between different catheter properties (NAPRTCS 2007 Annual Report 2008). Furth et al. also found no clear difference between single and double-cuff catheters concerning exit-site or tunnel infection frequency. Nor was there any difference in exit-site and tunnel infection incidence between coiled and straight catheters or between different exit-site orientations (up/

down/lateral) (Furth et al. 2000).

Modalities of PD

The first modality of PD was continuous ambulatory peritoneal dialysis (CAPD), which was replaced over time by continuous cycling peritoneal dialysis (CCPD); this first automated peritoneal dialysis form was developed to reduce the frequency of peritonitis (Price, Suki 1981). Tidal peritoneal dialysis (TPD) was introduced some years later;

in TPD, after the initial fill volume is instilled, a fraction of the volume is exchanged

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frequently using a cycler machine (Flanigan et al. 1991). It may provide advantages for children with outflow problems or outflow pain, and allows better purification for patients with high peritoneal membrane permeability (Hölttä et al. 2000a).

Automated peritoneal dialysis (APD) is performed overnight, the treatment time varying from 8 to 12 hours with 8 to 14 exchanges per night in CCPD. The fill volume in infants is usually 800―1000 ml/m² of BSA per exchange (Rönnholm, Holmberg 2006) and in older children larger volumes, from 1000 to 1200 or even up till 1400 ml/m² of BSA,are recommended (Fischbach, Warady 2009). The last fill left in the peritoneal cavity in the morning is usually half of the nightly fill volume on order to avoid discomfort, vomiting, and development of hernias. In addition to automated peritoneal dialysis (APD), anuric infants also need extra daytime exchanges to avoid hypervolemia (Rönnholm, Holmberg 2006).

Adequacy of PD

The adequacy of peritoneal dialysis is usually measured with a dialysate and urine collection test, from which Kt/V for urea and creatinine clearance (Crcl) are calculated (II. NKF-K/DOQI 2001). Kt/V urea was initially developed to illustrate the adequacy of hemodialysis but was later embraced for PD purification evaluations (Bargman 2006). In Kt/V, K represents clearance, t stands for observed time period (here 24 hours) and V for the volume of distribution (total body water). Thus, the clearance of urea is compared to total body water (TBW), in contrast to creatinine clearance which is compared to body surface area (BSA). Crcl describes the amount of creatinine that is removed from the blood over a time interval. According to the National Kidney Foundation (NKF) Work Group, based on the available evidence, the minimum target of weekly urea Kt/V should be 2.0 and of Crcl, 60 L/week per 1.73 m². If there are difficulties in achieving these targets, the Kt/V for urea should be the principle measure of adequacy. Urea Kt/V directly reflects protein metabolism and is also less influenced by alternations in residual renal function (II. NKF-K/DOQI 2001).

These measures characterize small and middle size molecule purification. Moreover, blood urea nitrogen, blood creatinine and phosphate are measures of purification; the lower these measures are, the better the purification is thought to be. The peritoneal equilibration test (PET) expresses peritoneal membrane function (Twardowski et al.

1987) and together with it and dialysate and urine collection tests it is possible to predict urea and creatinine clearances also in pediatric patients (Verrina et al. 1998, Warady et al. 2001).

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2.2.2.2 Complications of peritoneal dialysis

figure 5 Complications of PD.

2.2.2.2.1 Catheter-related complications

Catheter-related mechanical problems and infections are noteworthy causes of morbidity and treatment failure in children on PD, despite the advanced catheter models and PD techniques (Furth et al. 2000, Macchini et al. 2006). In 1995, the NAPRTCS reported the revision of 20% of the catheters in children of all ages (Neu et al. 1995), and in 2007 the revision of 19% (NAPRTCS 2007 Annual Report 2008). In a recent Italian study in children, where the patients’ mean age was six years, the catheter survival rate was 80% at one year, and 62% at two years on PD, and the incidence of catheter-related complications was one episode per 6.4 months on PD when peritonitis was included. Catheter survival was longer in children over five years compared to children less than two years of age. Single-cuff catheters had lower infection rates

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compared to double-cuff catheters (Macchini et al. 2006). Aksu et al. (2007) have reported a very low catheter complication rate of 1 episode per 24.7 patient-months and a high catheter survival rate of 92% at one year and 83% at 2 years in children between three months and 16 years (mean age eight years).

Mechanical problems

In the above mentioned Italian study, catheter obstruction constituted 13%, dislocation 9%, and leakage 6% of the complications when peritonitis was excluded (Macchini et al. 2006). In the NAPRTCS report of 2007, malfunction comprised 48% and leak 5% of complications also when peritonitis was not included (NAPRTCS 2007 Annual Report 2008). In the report of Aksu et al. (2007), dislocation yielded 9%, leakage and rotation both 5% of the complications, again when peritonitis was excluded.

Omentectomy has been shown to reduce obstruction rate and lengthen the survival time of the catheter (Macchini et al. 2006, Reissman et al. 1998, Rinaldi et al. 2004).

The surgical technique and an experienced team for catheter placement are the most critical factors for catheter survival (Macchini et al. 2006, Aksu et al. 2007).

Exit-site and tunnel infections

Exit-site infection diagnosis should be made if there is a purulent drainage from the exit-site, or notable pericatheter edema, redness, or/and tenderness locally. A positive bacterial culture is not required for the diagnosis of exit-site infections (Table 2, Schaefer et al. 1999b, Warady et al. 2000).

In a recent Italian study, exit-site infections (ESI) and tunnel infections (TI) were shown to be responsible for 59% of catheter-related complications when peritonitis was excluded (Macchini et al. 2006), whilst in the NAPRTCS report of 1995, ESI or TI was seen in 36% of children between 0 and 5 years (Neu et al. 1995). In contrast, the NAPRTCS report of 2007 demonstrated that ESI and TI comprised 18% of catheter- related complications when peritonitis was excluded (NAPRTCS 2007 Annual Report 2008). In the report of Aksu et al. (2007), ESI and TI proved to be the most common catheter complications (81% when peritonitis was not included), and these were more frequent in younger patients. On the other hand, Furth et al. (2000) had stated earlier that catheter characteristics, patient age, or race, had no influence on the risk of ESI or TI.

table 2. Exit-site infection scoring system. A score of ≥4 means infection. Purulent drainage, even alone, is an evidence of infection. Adapted from Schaefer et al. (1999b) and Piraino et al. (2005).

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2.2.2.2.2 Peritonitis

In children, fever and abdominal pain are considered too nonspecific as symptoms for the diagnosis of peritonitis. The diagnosis should be made if the dialysis effluent is cloudy, the white blood cell count is more than 100 per μL in the effluent, and at least 50% of the leucocytes are polymorphonuclear (Warady et al. 2000).

Peritonitis is a very potent cause of morbidity and the most important cause of PD failure despite reduced incidence of infections over the years (Chadha et al. 2010, Schaefer et al. 2007). Many reports demonstrate a higher incidence of peritonitis in younger children (Neu et al. 2002, NAPRTCS 2007 Annual Report 2008, Hölttä et al.

2000b, Honda et al. 1996, Hoshii et al. 2006). The NAPRTCS report of 2007 shows an annualized peritonitis rate of 0.79 (number of peritonitis per year) between 1992 and 1996 and a rate of 0.57 between 1997 and 2006. In children less than two years of age the rate during the whole follow-up period was 0.86 compared to 0.61 in children over twelve years (NAPRTCS 2007 Annual Report 2008). A recent report from Germany showed a peritonitis incidence of 0.85 episodes per patient-year in infants starting PD during the first year of life (Wedekin et al. 2010). Other risk factors for peritonitis are existing ESI or TI of the catheter, a higher degree of connections and spiking of the dialysate bags, and not using prophylactic antibiotics at the time of catheter placement (Chadha et al. 2010, Szeto et al. 2001, Gadallah et al. 2000).

Peritonitis is most commonly caused by bacteria, in particular gram-positive bacteria, that caused approximately 50―70% of the episodes in the early days of PD. With improved treatment protocols, the incidence of Gram positive peritonitis has been distinctly reduced, whilst the overall incidence of peritonitis has decreased.

Better connection technology on PD, prophylactic medication for nasal carriage of Staphylococcus aureus, good exit-site care, improved skills of the medical team, and training of the family are partly responsible for the decreased peritonitis rate (Macchini et al. 2006, Chadha et al. 2010, Piraino et al. 2003). The causative organisms of peritonitis, according to recent studies, are shown in Table 3.

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table 3. Causative organisms of peritonitis in children on PD.

2.2.2.2.3 Hernias

Hernias are frequent in PD patients, especially in small children, although the existing data is scarce concerning infants. Earlier studies report hernias in 23 to 40% of children of all ages, mostly inguinal and ventral ones (Hölttä et al. 1997, von Lilien et al. 1987, Khoury et al. 1991, Verrina et al. 1992). One later study reports hernias in 11.5% of children with a mean age of nine years at PD onset (Donmez et al. 2003).

Very few recent studies of children on PD report a prevalence of hernias.

Intraperitoneal pressure

Aranda et al. showed that intraperitoneal pressure (IPP) influences the frequency of hernias, and that IPP is lower in children compared to adults (Aranda et al. 2000).

Elevated IPP can cause discomfort, pain, gastrointestinal reflux, hernias, and also loss of ultrafiltration. IPP measurement is an important tool in prescribing dialysis treatment concerning tolerance and adequacy (Fischbach et al. 2003). Durand et al.

first presented the IPP measurement technique in adults (Durand et al. 1992) and Fischbach later applied it in children (Fischbach et al. 1994, Fischbach et al. 1996, Fischbach et al. 1996). The measurement itself is simple: the child rests in a supine position, the zero level is set in the patient’s mid-axillary line and the mean value of inspiration and expiration is used (see Fig.6) (Durand et al. 1992). Fischbach et al.

recommend a normal value for IPP of less than 18 cm of water, although between 5

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and 15 cm of water is acceptable, depending on the fill volume. The patient’s age, sex, and body mass index should also be taken into account (Fischbach et al. 2003).

figure 6 IPP measurement. Adapted from Durand et al. (1992).

2.2.2.2.4 Intravascular volume status Hypertension

Hypertension is a common problem seen in as many as 52 to 63% of children on PD (Tkaczyk et al. 2006, Hölttä et al. 2001, Donmez et al. 2003, Acar et al. 2008, Mitsnefes et al. 2003, Mitsnefes, Stablein 2005). According to NAPRTCS, 77% of the patients (both PD and HD) suffered from hypertension, of which 57% was uncontrolled and 20% controlled at the beginning of dialysis. Risk factors for hypertension included high blood pressure (BP) at baseline, young age, and acquired kidney disease as a cause for ESRF, and HD as dialysis mode. BP remained high in most patients during the first year on dialysis and medication did not correct the situation. However, the first months on dialysis seemed to be crucial for getting BP under control (Mitsnefes, Stablein 2005).

Hypovolemia

Hypotension and hypovolemia during dialysis may cause permanent brain or nervous system damage. Early cases in Finland reported severe hypovolemia during dialysis

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in small PD patients (Qvist et al. 2002, Valanne et al. 2004). One of these patients, with NPHS1, that experienced longer hypotensive periods, acquired permanent, severe visual impairment. There have been three reports on small children aged 1 to 5 years with anterior ischemic optic neuropathy as a consequence of hypovolemia or a period of low blood pressure values during PD. A permanent visual handicap was reported for all, although their hypovolemia and blood pressure levels were corrected (Bates et al. 1999, Chutorian et al. 2002, Lapeyraque et al. 2003). Two patients also had changes in their brain magnetic resonance imaging (MRI): one displayed periventricular white matter abnormalities and the other encephalomalasia and gliosis in the occipital cortex bilaterally. These changes suggest chronic hypoperfusion (Bates et al. 1999, Lapeyraque et al. 2003).

Heart ultrasound measures

Cardiovascular diseases are a significant reason for deaths and accounted for 32% of the deaths in children and young adults with ESRF in a single center study (Offner et al. 1999). Left ventricular hypertrophy (LVH) is often detected (45 to 75%) in pediatric PD and HD patients (Hölttä et al. 2001, Civilibal et al. 2009, Mitsnefes et al. 2000).

Left ventricular mass index (LVMI = left ventricular mass divided by body height^2.7) was also higher in children on dialysis compared to a control population in a couple of studies, reflecting a more frequent prevalence of LVH in dialysis patients (Robinson et al. 2005, Ten Harkel et al. 2009). Hölttä et al. found that children under 5 years of age displayed more frequent LVH when compared to older children (60% versus 30%) (Hölttä et al. 2001). In many studies on children with ESRF, the association between LVH (or high LVMI) and elevated blood pressure has been established (Hölttä et al.

2001, Ten Harkel et al. 2009, Mitsnefes et al. 2003, Mitsnefes et al. 2001). There are studies indicating that volume overload and long-lasting hypertension further the development of LVH (Groothoff et al. 2005, Mitsnefes et al. 2003). In some studies the hemoglobin levels were lower in the patients with LVH compared to either patients without LVH or controls (Civilibal et al. 2009, Mitsnefes et al. 2000). Quantification of the left ventricular mass (LVM) is always an estimation which is based on formulas that fit ventricular shape to geometric figures (Vuille, Weyman 1994). Adjustment of LVM to body size can also be carried out in many ways such as by comparing LVM to height, BSA, or weight (Levy et al. 1987, Foppa et al. 2005). Additionally, defining the cut-off point between normal LVM compared to body size and LVH is a controversial matter and different methods yield diverse results regarding the prevalence of patients with LVH (Foppa et al. 2005).

Bioelectrical impedance analysis

Bioelectrical impedance analysis (BIA) is a non-invasive method to examine body composition and is based on different electrical properties of tissues (see Fig.7). First utilized in body fat evaluations, BIA is typically used to measure lean mass and body fluid volumes such as total body water (TBW). The quantities measured with BIA are reactance (Xc) that reflects body cell mass and resistance (R) that is inversely proportional to body water volume. The measurement can be done with a specific

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electric current frequency or with several frequencies. At 50 kHz the current flows through both extra and intracellular fluid and BIA value correlates to TBW, but the value is in reality representing a weighted sum of extra-cellular water (ECW) and intra-cellular water (ICW) volume resistivities (Kyle et al. 2004, Ellis et al. 1999).

Low frequencies do not pass the cell membrane as well as higher frequencies and thus better reflect the ECW (Deurenberg et al. 1995). To distinguish TBW, ECW and ICW, a multi-frequency device must be used (Kyle et al. 2004). An increased ECW or ECW/TBW ratio may be due to edema or malnutrition in a patient. Basile et al.

(2007) have studied and developed dry weight prediction equations for adults on HD, whilst Edefonti et al. (2001) have used BIA in the evaluation of the nutritional status of children on PD. Accordingly, Wühl et al. (1996) have defined equations for calculating TBW in children on PD or HD at 50 kHz. The median age of these patients was 11.9 years (range 4.1―20.3). Later, Brooks et al. (2008) studied the correlation between BIA and TBW as well as BIA and blood pressure in older children on HD, although ECW evaluations or equations were not performed in these studies. The reference values of TBW and ECW for small children, especially for infants, do not yet exist which has restricted the use of BIA in small dialysis patients.

figure 7 A) BIA measurement, wrist and ankle placement of electrodes. Adapted from Chamney et al. (2002). B) Theoretical BIA current flow. Modeled after Chamney et al.

(2002).

2.2.2.3 Mortality in children on peritoneal dialysis

The mortality of children on PD is typically 5 to 20% (Shroff et al. 2006, Hölttä et al. 1997, NAPRTCS 2007 Annual Report 2008, Hölttä et al. 2000b, Rees 2002).

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The youngest patients have the lowest survival rate (Verrina et al. 2004, NAPRTCS 2007 Annual Report 2008). According to the NAPRTCS report from 2007, the most frequent causes of death were cardiopulmonary problems and different types of infection (NAPRTCS 2007 Annual Report 2008). Co-morbidities such as cardiac, gastrointestinal, and metabolic disorders were associated with 76% of the deaths in dialysis children in the study by Shroff et al. The most common causes of death were brain insults and various infections. The youngest patients were in greater risk for death; the mortality rate was almost threefold in children under five years of age compared to older ones (Shroff et al. 2006).

2.2.2.4 Growth in children on peritoneal dialysis

Growth in children with ESRF has been a significant concern since dialysis and transplantation in children began (Stefanidis et al. 1983). Between detection of renal disease and initiation of dialysis, growth deterioration has been demonstrated in most children in a study of Lewis et al. (2007). At the beginning of dialysis, 54%

of the patients were under the fifth percentile in height Z scores (Lewis et al. 2007).

In the NAPRTCS report of 2007, the mean height standard deviation score (hSDS) in children initiating dialysis was -2.55 in children less than two years of age, and -1.94 in children between 2 and 5 years. PD patients are smaller than HD patients and boys are proportionally smaller than girls at PD initiation (NAPRTCS 2007 Annual Report 2008). Several other studies confirm these results: in the report by Shroff et al. (2006), the mean hSDS at dialysis start was -2.8 in 98 children between birth and 16 years of age, whilst children under five had a mean hSDS of only -3.6 at initiation of dialysis. In the study by Cansick et al. (2007), a mean hSDS of -2.1 was seen in prepubertal children starting PD at a mean age of 2.8 years. Therefore, these children are already short statured when entering dialysis programs. Accordingly, the growth is poorest in young children.

Healthy children grow fast during the first two years, thus growth impairment in infancy has much consequence. Growth during dialysis has not improved as much as could have been expected with adequate nutrition and careful management of renal bone disease (Stefanidis, Klaus 2007). In a European multi-center study, over 18 months, the mean hSDS did not change notably during treatment (Schaefer et al.

1999a). The NAPRTCS reports changes of -0.11 and -0.15 in the mean height Z-scores one and two years after the initiation of dialysis for all children on dialysis. Only a minimal change of -0.07 in height Z-score was seen in PD patients one year after baseline and no change between one and two years was seen. In HD patients, changes of -0.18 and -0.31 one and two years after PD onset were detected (NAPRTCS 2007 Annual Report 2008). In the study of Cansick et al., catch-up growth was found in some patients less than 2 years of age during the first year of dialysis (Cansick et al. 2007). In a Finnish study, catch-up growth was observed in 62% of children less than 5 years of age during a 9-month period (Hölttä et al. 2000b). Adequate nutrition, mostly with dietary energy and protein supplementation via nasogastric tube or gastrostomy and strict management of phosphorus control are essential in

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reaching good growth in children on dialysis (Cansick et al. 2007, Kari et al. 2000).

Recombinant human growth hormone (rhGH) is rarely used in children on PD, in only 16%, according to the European Dialysis and Transplantation Association (ERA- EDTA) Registry. Its use has not increased during the last years (Lewis et al. 2007).

The NAPRTCS reported that 25% of PD patients and 14% of HD patients received rhGH during dialysis (Neu et al. 2002). Especially in infants, sufficient nutrition is the major factor in assuring growth. The management of hyperphosphatemia, hyperparathyroidism, and acidosis are crucial, as well. If the child with ESRF is small (hSDS <-1.88) or growth lags behind (height velocity <-2 SDS) despite optimal nutrition and medication, rhGH therapy should be started. An early administration of rhGH has been recommended but infants were not discussed separately (Stefanidis, Klaus 2007, Mahan et al. 2006).

It has been demonstrated that children with residual renal function (RRF) experience better growth on PD. Catch-up growth was seen in 58% of RRF patients compared to 17% of anuric patients in the study of Chadha et al.: about one third of their patients had rhGH treatment in both groups (RRF and anuric pt.) (Chadha et al. 2001). Poor growth has been associated with increased morbidity and mortality, where patients with growth failure display about a threefold risk of death compared to those with normal growth (Furth et al. 2002).

Target height (parent specific mean hSDS) takes the mean height of the local population and the height of the parents into account. It gives an estimate of the predicted height of the child and deviations of more than ±2 SDS point to some disease or disturbance (Sorva et al. 1989).

2.2.2.5 Hemodialysis

Hemodialysis is less used in small children compared to older ones. Only 7% of ESRF patients under two years of age were treated on HD compared to 32% in all children with ESRF in North America between 1992 and 2007 (2006 Annual Report of NAPRTCS 2007). In Finland between 1990 and 2008, only 1% of children under two and 21% of all children with ESRF were treated with HD as first treatment mode (Finnish Registry for Kidney Diseases 2009).

In the USA, the vascular access of HD has been an external central catheter in 69─84% of pediatric patients since the 1990s (NAPRTCS 2007 Annual Report 2008). In Finland, HD access in children is typically a dual-lumen venous catheter in the jugular or subclavian vein. Arteriovenous (AV) fistulas have been the most common way of vascular access in Europe. However, especially in infants, the construction of an AV fistula is challenging (Fischbach et al. 2005). The blood is cleansed of waste products with extracorporeal perfusion by a HD machine. At the same time, excess water is removed by ultrafiltration. HD treatment is normally done at least thrice per week in infants (Fischbach et al. 2005). Between treatment days anuric and oliguric patients are restricted regarding their intake of liquids to avoid hypervolemia because only a limited amount of ultrafiltration can be achieved during each HD session. Intensified daily HD has been used and studied in children as well. Fischbach et al. suggested

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in 2006 that daily HD could improve growth in children (Fischbach et al. 2006), and they later demonstrated that daily online hemodiafiltration dialysis, which includes both daily dialysis and convective flow added to HD, improves growth in children (Fischbach et al. 2010).

2.3 Neurological development and complications in children with end-stage renal failure

2.3.1 Neuromotor function evaluations

There are at least 15 distinct instruments with which neuromotor function can be evaluated in infants (Heineman, Hadders-Algra 2008). In Table 4, four different methods of assessment are presented, two of each kind. The age range of children that may be evaluated with these instruments varies from birth to four months and between 0 to 3.5 years. All these methods of assessment are aimed at distinguishing those infants developing within the normal range from the ones with a deviating neuromotor condition. These instruments differ not only in approach but also in validity and reliability. Three different validity characteristics, 1) constructive validity, that is the ability of a test to identify the measure that it proposes to identify, 2) concurrent validity, the degree to which a result from one test agree with a result from a different test, and 3) predictive validity, the ability to predict neurological outcome of the patient, are presented in Table 4. Intra and inter-observer reliability properties of these instruments are also shown in the table. The purpose of the assessment may be, 1) discriminative, to distinguish normal development from abnormal, 2) evaluative, to notice changes in the development or 3) predictive, to predict neurological outcome.

Specifying the goal that the assessment must achieve is important for choosing the right method of assessment for each patient group and survey (Heineman, Hadders- Algra 2008).

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table 4. Different instruments for evaluation of neuromotor function in infants.

Modified after Heineman and Hadders-Algra (2008).

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2.3.2 Neuropsychological and cognitive performance tests

In older children, at least five years of age, different neuropsychological tests can be used to evaluate neurodevelopment and cognition. Fennell et al. and Crocker et al.

used, among others, the Wide Range Achievement Test, Beery-Butenica Development Test of Visual Motor Integration to evaluate the neuropsychology of children with chronic renal failure (Fennell et al. 1990, Crocker et al. 2002). A Developmental Neuropsychological Assessment (NEPSY) and its extension NEPSY-II have been used for children with renal transplantation in Finland (Qvist et al. 2002, Haavisto et al. submitted). NEPSY can be used for children between 3 and 12 years. This instrument describes the patient’s attention and executive functions such as self- regulation and flexibility in thinking, language and communication skills, sensor motor and visuospatial processing as well as memory functions and learning abilities (Korkman 1988). NEPSY-II is an extended version of NEPSY, can be used up to age 16 and also tests social perception (Korkman et al. 2007).

Intelligence tests have also been used for Finnish pediatric renal and heart transplantation patients (Qvist et al. 2002, Haavisto et al. submitted, Haavisto et al.

2010). These study groups used the revised Wechsler Intelligence Scale for Children (WISC-R), which is suitable for children aged seven or more and is a modern IQ test (Wechsler 1974). The Wechsler Preschool and Primary Scale of Intelligence, Editions I-III (WPPSI─I-III), has been developed after WISC and can be used in children between two and a half and seven years (Wechsler 2003). The same IQ tests were used by Fennel et al., Crocker et al., and Madden et al. in childhood chronic renal failure (Fennell et al. 1990, Crocker et al. 2002, Madden et al. 2003). However, these wider neuropsychological and IQ tests can not be used in infants.

Hellbrügge et al. have developed a Munich Functional Developmental Diagnostic test (MFED) to evaluate functional development in children between one to three years (Hellbrügge et al. 1978). MFED has been used to define early cognitive development in Finnish children exposed to alcohol during the fetal period (Autti- Rämö, Granström 1991a).

2.3.3 Neurological development

There are very few studies into the neurological development of infants on peritoneal dialysis. An early literature review by Polinsky et al. in 1987 showed developmental delay in 84% of children dialyzed in infancy. After successful renal transplantation, delay was seen in 31%. Aluminum load from prior phosphate binders, hyperparathyroidism, malnutrition, and psychosocial problems were suspected to influence development (Polinsky et al. 1987). Later, Honda et al. reported low developmental quotients at the end of PD in 69% of Japanese patients less than two years of age at PD initiation (Honda et al. 1995). Geary and Haka-Ikse showed better results in infants with ESRF, 41% of whom had developmental delay (Geary, Haka-Ikse 1989). Warady et al. reported neurodevelopmental delay at the age of one year in only 21% of children on PD.

However in their study, patients with extra renal or neurological disease, as well as two sepsis patients who died before one year of age (18%), were not included in the

Peritoneal dialysis and neurological outcome in infants and small children